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Longitudinal changes in CSF biomarkers
Oral O1-05: Disease Mechanisms I subsequent Aß1-42 declines, tau/Aß1-42 ratio increases, and other brain imaging and fluid biomarker changes associated with the asymptomatic stages in PS1 E280A and other EOAD-causing mutation carriers–and to capitalize on this information in the evaluation of presymptomatic EOAD treatments.
O1-04-07
DIETS ASSOCIATED WITH TYPE 2 DIABETES AND INSULIN RESISTANCE AFFECT CSF MEDIATORS OF BETA-AMYLOID CLEARANCE AND TOXICITY
Suzanne Craft1, Thomas Montine2, Laura Baker1, Jennifer Carter1, Pattie Green1, Charles Wilkinson1, 1VA Puget Sound/University of Washington, Seattle, Wash., United States; 2University of Washington, Seattle, Washington. Background: Diets high in saturated fats and simple carbohydrates increase the risk of diabetes and insulin resistance, and are also linked to Alzheimer’s disease and mild cognitive impairment (AD/MCI). We reported previously that dietary intervention modulated cerebrospinal fluid amyloid beta (CSF Abeta42). The present study examined diet effects on lipoprotein-free Abeta42 and 40, which may have greater cytotoxicity than lipoprotein-associated isoforms, and on apolipoprotein E (APOE), insulin, and F2-IsoProstane (F2IsoP) which modulate Abeta clearance and toxicity. Methods: Adults with amnestic MCI (n ¼ 29, mean age ¼ 67.6) and healthy adults (n ¼ 20, mean age ¼ 69.2) received one of two isocaloric diets: a high saturated fat/high glycemic diet (HIGH: total fat 45%, 25% SF, < 70 GI), or a low saturated fat/low glycemic diet (LOW: total fat 25%, < 8% SF, < 55 GI) for 4 weeks. Fasting CSF collection occurred before and following the diet intervention. Lipoprotein-free Abeta and APOE were measured with density-gradient centrifugation and ELISA. Results: Baseline lipoprotein-free CSF Abeta40 and Abeta42 were higher for adults with MCI (ps ¼ 0.03 and 0.08), and APOE-e4 carriers had higher lipoprotein-free APOE levels than non-carriers independent of diagnosis (p ¼ 0.0001). The LOW diet lowered and the HIGH diet increased lipoprotein-free Abeta42 independent of diagnosis and e4-carrier status (p ¼ 0.01). Lipoprotein-free Abeta42 and Abeta40 reductions, and CNS insulin elevations, were correlated with reductions in lipoprotein-free apoE for LOW normal adults (p < 0.05). For the LOW MCI group, increased CSF insulin was associated with reduced lipoprotein-free Abeta42 and 40 levels (ps ¼ 0.005 and 0.03). The LOW diet reduced and the HIGH diet increased CSF F2-IsoP levels for both groups (p < 0.01), and HIGH diet increases were associated with reduced CSF insulin levels (p ¼ 0.05). Conclusions: The LOW diet reduced lipoprotein-free Abeta42 levels with correlated changes in CSF insulin and lipoprotein-free APOE, both of which may play a role in Abeta clearance. Conversely, the HIGH diet increased lipoprotein-free Abeta42 levels in correspondence with reduced insulin and elevated F2-IsoPs. These results suggest that diet plays an important role in Abeta’s regulation, in part through modulation of its association to lipoproteins that mediate its clearance and toxicity. Diet effects on CNS insulin and free radical injury may also impact AD pathology.
O1-04-08
LONGITUDINAL CHANGES IN CSF BIOMARKERS
Sanna-Kaisa Herukka1, Toni T. Sepp€al€a2, P€aivi Hartikainen3, Seppo Helisalmi4, Hilkka Soininen5, Anne Koivisto6, 1University of Eastern Finland, Kuopio, Finland; 2University of Eastern Finland, Kuopio; 3Kuopio University Hospital, Kuopio; 4University of Eastern Finland, Kuopio; 5 Univrsity of Eastern Finland, Kuopio; 6Kuopio University Hospital, Kuopio. Background: Longitudinal changes of Alzheimer’s disease CSF biomarkers have been studied resulting in inconsistent conclusions and little is known of their variation during different stages of the disease course. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. Methods: One hundred and thirty-one memory clinic patients (56 AD, 57 MCI, 10 other neurological disorders, eight unimpaired subjects) underwent a clinical follow-up with repeated MMSE tests and two lumbar punctures with a median interval of 3
S103
years. Levels of CSF Ab42, tau and p-tau-181 were measured using commercially available ELISA. Results: During the follow-up, 21 MCI patients progressed to AD, 26 subjects remained stable. 56 subjects had AD already at the baseline. Subjects with the most rapid MMSE decline rate had the lowest baseline CSF Ab42, highest tau and highest p-tau concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau concentration was seen in AD-AD patients (p ¼ 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p ¼ 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p ¼ 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau correlated with the MMSE decrease rate in AD subjects (r ¼ 0.579, p < 0.001). The CSF Ab42 decreased in the AD-AD group (decrease of 11.9 pg/ml/year, p < 0.001). Conclusions: Hyperphosphorylated tau decreases in the late stages of the AD process. The decrease of p-tau may correlate to clinical cognitive functioning, probably reflecting neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients in the preclinical stage of the disease.
SUNDAY, JULY 17, 2011 ORAL O1-05 DISEASE MECHANISMS I O1-05-01
APOE4 PLAYS A ROLE IN ABETA-MEDIATED SYNAPSE LOSS IN ALZHEIMER’S DISEASE
David Holtzman1, Bradley Hyman2, Virginia Lee3, Tara Spires-Jones4, Robert Koffie5, Tadafumi Hashimoto2, Daniel Joyner2, Steven Hou2, Katherine Kopeikina6, Matthew Frosch2, 1Washington University School of Medicine, St. Louis, Missouri; 2Massachusetts General Hospital, Charlestown, Massachusetts; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 4Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass., United States; 5Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts; 6Massachusetts General Hospital, Boston University School of Medicine, Charlestown, Massachusetts. Background: The Apolipoprotein E (APOE) e4 gene is the most important genetic risk factor for late onset Alzheimer’s disease (AD), but the link between APOE e4 and neurodegeneration remains unclear. Recent data from mouse models and cell culture has shown that oligomeric forms of amyloidb are present at synapses where they contribute to synaptic dysfunction and loss, but the role of Ab in synapse loss in human AD and its relationship to APOE genotype remains an important question in the field. Methods: We have used size exclusion chromatography, confocal microscopy, and the advanced imaging technique array tomography in cell culture, mouse models, and human AD brain to test the hypothesis that APOE e4 acts through increasing levels of toxic oligomeric Ab (oAb) and targeting it to synapses. Using array tomography, we also explore the downstream effects of targeting oAb to synapses by examining the effects of oAb on synaptic composition. Results: We find that APOE e4 substantially increases levels of oAb in the brain and increases association of oAb with synapses in the brain and in culture, indicating that APOE e4 may target oAb to synapses where it is toxic. Synapses contacted by oAb are abnormally small. APOE isoform has an effect on synapse loss with e4 associated with more synapse loss and more oAb at synapses. These data show that APOE4 enhances oAb’s toxicity both by increasing oAb levels and by directing it to synapses where it causes shrinkage, changes in synaptic proteins, and ultimately synapse collapse. Conclusions: These results provide a link between APOE e4 genotype and synapse loss, the strongest correlate of cognitive decline in AD. These findings support the hypothesis that APOE e4 facilitates transport of oAb to synapses where it is toxic and further support the idea that oAb plays an important role in synaptic damage not only in animal models of Ab toxicity, but in human AD. Since synapses can reform after damage, blockade of the oAb-apoE interaction could be a therapeutic approach to preventing Ab mediated synapse loss in AD.
O1-04-07
DIETS ASSOCIATED WITH TYPE 2 DIABETES AND INSULIN RESISTANCE AFFECT CSF MEDIATORS OF BETA-AMYLOID CLEARANCE AND TOXICITY
Suzanne Craft1, Thomas Montine2, Laura Baker1, Jennifer Carter1, Pattie Green1, Charles Wilkinson1, 1VA Puget Sound/University of Washington, Seattle, Wash., United States; 2University of Washington, Seattle, Washington. Background: Diets high in saturated fats and simple carbohydrates increase the risk of diabetes and insulin resistance, and are also linked to Alzheimer’s disease and mild cognitive impairment (AD/MCI). We reported previously that dietary intervention modulated cerebrospinal fluid amyloid beta (CSF Abeta42). The present study examined diet effects on lipoprotein-free Abeta42 and 40, which may have greater cytotoxicity than lipoprotein-associated isoforms, and on apolipoprotein E (APOE), insulin, and F2-IsoProstane (F2IsoP) which modulate Abeta clearance and toxicity. Methods: Adults with amnestic MCI (n ¼ 29, mean age ¼ 67.6) and healthy adults (n ¼ 20, mean age ¼ 69.2) received one of two isocaloric diets: a high saturated fat/high glycemic diet (HIGH: total fat 45%, 25% SF, < 70 GI), or a low saturated fat/low glycemic diet (LOW: total fat 25%, < 8% SF, < 55 GI) for 4 weeks. Fasting CSF collection occurred before and following the diet intervention. Lipoprotein-free Abeta and APOE were measured with density-gradient centrifugation and ELISA. Results: Baseline lipoprotein-free CSF Abeta40 and Abeta42 were higher for adults with MCI (ps ¼ 0.03 and 0.08), and APOE-e4 carriers had higher lipoprotein-free APOE levels than non-carriers independent of diagnosis (p ¼ 0.0001). The LOW diet lowered and the HIGH diet increased lipoprotein-free Abeta42 independent of diagnosis and e4-carrier status (p ¼ 0.01). Lipoprotein-free Abeta42 and Abeta40 reductions, and CNS insulin elevations, were correlated with reductions in lipoprotein-free apoE for LOW normal adults (p < 0.05). For the LOW MCI group, increased CSF insulin was associated with reduced lipoprotein-free Abeta42 and 40 levels (ps ¼ 0.005 and 0.03). The LOW diet reduced and the HIGH diet increased CSF F2-IsoP levels for both groups (p < 0.01), and HIGH diet increases were associated with reduced CSF insulin levels (p ¼ 0.05). Conclusions: The LOW diet reduced lipoprotein-free Abeta42 levels with correlated changes in CSF insulin and lipoprotein-free APOE, both of which may play a role in Abeta clearance. Conversely, the HIGH diet increased lipoprotein-free Abeta42 levels in correspondence with reduced insulin and elevated F2-IsoPs. These results suggest that diet plays an important role in Abeta’s regulation, in part through modulation of its association to lipoproteins that mediate its clearance and toxicity. Diet effects on CNS insulin and free radical injury may also impact AD pathology.
O1-04-08
LONGITUDINAL CHANGES IN CSF BIOMARKERS
Sanna-Kaisa Herukka1, Toni T. Sepp€al€a2, P€aivi Hartikainen3, Seppo Helisalmi4, Hilkka Soininen5, Anne Koivisto6, 1University of Eastern Finland, Kuopio, Finland; 2University of Eastern Finland, Kuopio; 3Kuopio University Hospital, Kuopio; 4University of Eastern Finland, Kuopio; 5 Univrsity of Eastern Finland, Kuopio; 6Kuopio University Hospital, Kuopio. Background: Longitudinal changes of Alzheimer’s disease CSF biomarkers have been studied resulting in inconsistent conclusions and little is known of their variation during different stages of the disease course. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. Methods: One hundred and thirty-one memory clinic patients (56 AD, 57 MCI, 10 other neurological disorders, eight unimpaired subjects) underwent a clinical follow-up with repeated MMSE tests and two lumbar punctures with a median interval of 3
S103
years. Levels of CSF Ab42, tau and p-tau-181 were measured using commercially available ELISA. Results: During the follow-up, 21 MCI patients progressed to AD, 26 subjects remained stable. 56 subjects had AD already at the baseline. Subjects with the most rapid MMSE decline rate had the lowest baseline CSF Ab42, highest tau and highest p-tau concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau concentration was seen in AD-AD patients (p ¼ 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p ¼ 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p ¼ 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau correlated with the MMSE decrease rate in AD subjects (r ¼ 0.579, p < 0.001). The CSF Ab42 decreased in the AD-AD group (decrease of 11.9 pg/ml/year, p < 0.001). Conclusions: Hyperphosphorylated tau decreases in the late stages of the AD process. The decrease of p-tau may correlate to clinical cognitive functioning, probably reflecting neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients in the preclinical stage of the disease.
SUNDAY, JULY 17, 2011 ORAL O1-05 DISEASE MECHANISMS I O1-05-01
APOE4 PLAYS A ROLE IN ABETA-MEDIATED SYNAPSE LOSS IN ALZHEIMER’S DISEASE
David Holtzman1, Bradley Hyman2, Virginia Lee3, Tara Spires-Jones4, Robert Koffie5, Tadafumi Hashimoto2, Daniel Joyner2, Steven Hou2, Katherine Kopeikina6, Matthew Frosch2, 1Washington University School of Medicine, St. Louis, Missouri; 2Massachusetts General Hospital, Charlestown, Massachusetts; 3University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 4Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass., United States; 5Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts; 6Massachusetts General Hospital, Boston University School of Medicine, Charlestown, Massachusetts. Background: The Apolipoprotein E (APOE) e4 gene is the most important genetic risk factor for late onset Alzheimer’s disease (AD), but the link between APOE e4 and neurodegeneration remains unclear. Recent data from mouse models and cell culture has shown that oligomeric forms of amyloidb are present at synapses where they contribute to synaptic dysfunction and loss, but the role of Ab in synapse loss in human AD and its relationship to APOE genotype remains an important question in the field. Methods: We have used size exclusion chromatography, confocal microscopy, and the advanced imaging technique array tomography in cell culture, mouse models, and human AD brain to test the hypothesis that APOE e4 acts through increasing levels of toxic oligomeric Ab (oAb) and targeting it to synapses. Using array tomography, we also explore the downstream effects of targeting oAb to synapses by examining the effects of oAb on synaptic composition. Results: We find that APOE e4 substantially increases levels of oAb in the brain and increases association of oAb with synapses in the brain and in culture, indicating that APOE e4 may target oAb to synapses where it is toxic. Synapses contacted by oAb are abnormally small. APOE isoform has an effect on synapse loss with e4 associated with more synapse loss and more oAb at synapses. These data show that APOE4 enhances oAb’s toxicity both by increasing oAb levels and by directing it to synapses where it causes shrinkage, changes in synaptic proteins, and ultimately synapse collapse. Conclusions: These results provide a link between APOE e4 genotype and synapse loss, the strongest correlate of cognitive decline in AD. These findings support the hypothesis that APOE e4 facilitates transport of oAb to synapses where it is toxic and further support the idea that oAb plays an important role in synaptic damage not only in animal models of Ab toxicity, but in human AD. Since synapses can reform after damage, blockade of the oAb-apoE interaction could be a therapeutic approach to preventing Ab mediated synapse loss in AD.